rs121918527

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5

The NM_031407.7(HUWE1):c.12559C>T(p.Arg4187Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 111,071 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Consequence

HUWE1
NM_031407.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 6.85

Variant links:

Genes affected

HUWE1 (HGNC:30892): (HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1) This gene encodes a protein containing a C-terminal HECT (E6AP type E3 ubiquitin protein ligase) domain that functions as an E3 ubiquitin ligase. The encoded protein is required for the ubiquitination and subsequent degradation of the anti-apoptotic protein Mcl1 (myeloid cell leukemia sequence 1 (BCL2-related)). This protein also ubiquitinates the p53 tumor suppressor, core histones, and DNA polymerase beta. Mutations in this gene are associated with Turner type X-linked syndromic cognitive disability. [provided by RefSeq, Aug 2013]

HUWE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HUWE1. . Gene score misZ 8.8732 (greater than the threshold 3.09). GenCC has associacion of gene with syndromic intellectual disability, intellectual disability, X-linked syndromic, Turner type, non-syndromic X-linked intellectual disability.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.882

PP5

Variant X-53535474-G-A is Pathogenic according to our data. Variant chrX-53535474-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 10678.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=4}. Variant chrX-53535474-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HUWE1	NM_031407.7 linkuse as main transcript	c.12559C>T	p.Arg4187Cys	missense_variant	81/84	ENST00000262854.11	NP_113584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11 linkuse as main transcript	c.12559C>T	p.Arg4187Cys	missense_variant	81/84	1	NM_031407.7	ENSP00000262854	P2	Q7Z6Z7-1

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

111071

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33303

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000967

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000180

AC:

AN:

111071

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33303

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000967

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000189

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Intellectual disability, X-linked syndromic, Turner type

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Lab, CHRU Brest	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 14, 2023	Criteria applied: PS2_MOD;PS4_MOD,PM5,PS3_SUP,PM2_SUP,PP1,PP2 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2008	- -

not provided

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 15, 2021	This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this variant affects HUWE1 protein function (PMID: 29118367). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HUWE1 protein function. ClinVar contains an entry for this variant (Variation ID: 10678). This variant is also known as c.12229C>T (p.R4077C). This variant has been observed in individual(s) with intellectual disability (PMID: 18252223, 19377476). This sequence change replaces arginine with cysteine at codon 4187 of the HUWE1 protein (p.Arg4187Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2024	Identified in multiple male family members with intellectual disability in published literature (PMID: 18252223); Published functional studies demonstrate a damaging effect on protein function (PMID: 28445732, 34314700); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19377476, 23871722, 29180823, 29307790, 27130160, 29118367, 33948573, 32336296, 34314700, 28445732, 36111624, 37167062, 38021253, 18252223) -

Non-syndromic X-linked intellectual disability

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 25, 2020

A hemizygous missense variant was identified, NM_031407.6(HUWE1):c.12559C>T in exon 81 of 84 of the HUWE1 gene. This substitution is predicted to create a major amino acid change from an arginine to a cysteine at position 4187 of the protein, NP_113584.3(HUWE1):p.(Arg4187Cys). The arginine at this position has very high conservation (100 vertebrates, UCSC), and is located within the HECT domain. In silico software predicts this variant to be damaging (Polyphen, SIFT, CADD, Mutation Taster) and the variant is not present in the gnomAD population database. It has been previously reported in patients with X-linked intellectual disability (ClinVar; Hu, H. et al. (2016)). It has also been shown to segregate with disease in one family (Froyen, G. et al. (2008)). In addition, functional studies showed decreased DNA repair capacity and hypersensitivity to oxidative stress in patient lymphoblastoid cells (Bosshard, M. et al. (2017)). A different variant in the same codon resulting in a change to a histidine has been reported as likely pathogenic (ClinVar; Niranjan, T. et al. (2015)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Benign

0.96

DEOGEN2

Benign

0.38

.;T;T

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;.;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.88

D;D;D

MetaSVM

Uncertain

0.38

MutationAssessor

Pathogenic

3.3

.;M;M

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-6.6

.;D;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.0010

.;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.65

MutPred

0.60

.;Loss of catalytic residue at R4187 (P = 0.0822);Loss of catalytic residue at R4187 (P = 0.0822);

MVP

0.92

MPC

1.8

ClinPred

1.0

GERP RS

5.4

Varity_R

0.93

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over